In studies completed in the last 5-year grant period, we found considerable evidence that hypoxic-ischemic injury may be involved in the pathogenesis of diabetic polyneuropathy. Endoneurial microvessel alterations also were found. Endoneurial myoinositol level was not significantly decreased in conventionally treated diabetics, but fructose and sorbitol levels were, and the latter was linearly associated with severity of neuropathy. In the next 5 years we will: 1) continue to study human sural nerves, recruiting more diabetics without and with mild and severe neuropathy and more controls 40 to 65 yr old; 2) study ganglia and segmental nerves of patients with diabetic truncal radiculopathy; and 3) study the neuropathologic, morphometric, and teased-fiber abnormalities and microvascular reactions from hyperglycemia, hypoglycemia, chronic hypoxia, repeated fiber degeneration, and permanent nerve transection. In (3) studies we seek to recognize stereotypic reactions to injury, specific reactions we can then look for in nerves of diabetics. The possible toxic effect of aminoguanidine will also be studied. Determination of the Index of Pathology (Ip) of sural nerves in controls will allow us to develop age- specific normal values. Comparing Ip in diabetics to Ip in controls will allow us to develop minimal neuropathologic criteria for diabetic polyneuropathy and to judge if diabetics have neuropathy and the severity of their neuropathy. The quantitated neuropathologic abnormalities will be compared to minimal clinical (Project 36), risk factors (Project 36), metabolites (Project 37), microvessel alteration (Project 37), and functional alterations (Projects 31 and 38). The microvessel alterations will be tested against neuropathologic alterations and will be used to model whether microhypoxia-ischemia has occurred. One manifestation of human diabetic neuropathy, sudomotor abnormality, has been reproduced in streptozocin diabetes. This can be prevented and ameliorated by strict control of glycemia. We now test whether it is also ameliorated by aldose reductase inhibitors (ARI) or gangliosides. The ultrastructure of nerve terminals to sweat glands in controls and diabetics will be studied. Major advances are expected because the studies are already in progress, other investigators are involved, and tissue is already available.